ClinVar

Description

The PTPN11 c.836A>G; p.Tyr279Cys variant (rs121918456) is reported in the literature in numerous individuals affected with Noonan syndrome and LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines (Begic 2014, Digilio 2004, Legius 2002, Quaio 2013, Sarkozy 2004, Tartaglia 2002, Wang 2014). This is a recurrent variant reported to cosegregate with disease in families (Begic 2014, Legius 2002) and also observed de novo (Begic 2014, Digilio 2004, Wang 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13328), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 279 is highly conserved and interacts with an active site loop required for catalysis (Kontaridis 2006, Qiu 2014), and biochemical analyses demonstrate strongly reduced phosphatase activity of the p.Tyr279Cys variant (Hanna 2006, Qiu 2014). In both cultured cells and mice, the p.Tyr279Cys variant exhibits a dominant negative effect on Erk/MAPK signaling (Kontaridis 2006, Marin 2011), and the mouse model of PTPN11 p.Tyr279Cys recapitulates physiological symptoms of human LEOPARD syndrome, including skeletal abnormalities and hypertrophic cardiomyopathy (Marin 2011). Additionally, another variant at this codon (p.Tyr279Ser) has been reported in an individual with symptoms of LEOPARD syndrome (Sarkozy 2004), reiterating its functional importance. Based on available information, the p.Tyr279Cys variant is considered to be pathogenic. References: Begic F et al. Leopard syndrome: a report of five cases from one family in two generations. Eur J Pediatr. 2014 Jun;173(6):819-22. Digilio MC et al. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. 2004 Feb;70(2):95-8. Hanna N et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006 May 1;580(10):2477-82. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. Legius E et al. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002 Aug;39(8):571-4. Marin TM et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011 Mar;121(3):1026-43. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 Mar 14;14:10. Quaio CR et al. Tegumentary manifestations of Noonan and Noonan-related syndromes. Clinics (Sao Paulo). 2013;68(8):1079-83. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. Wang Y et al. Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han. Int J Cardiol. 2014 Jul 1;174(3):e101-4.